A major goal in surgery, as well as treatment of major tissue damage, is to avoid or minimize bleeding to ensure the formation of stable and secure haemostatic plugs that are not easily dissolved by fibrinolytic enzymes. It is of importance to ensure quick and effective formation of such plugs or clots, which should be limited in their extent to avoid unwanted haemostatic consequences. Antifibrinolytic agents are widely used to prevent fibrinolysis and reduce blood loss associated with trauma, in major surgery, and in response to bleeding associated with pathologies such as menorrhagia.
Currently, two synthetic lysine analogs, epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA), are the only antifibrinolytics in widespread commercial use to control bleeding. These agents competitively inhibit activation of Plasminogen to Plasmin, a proteolytic enzyme that acts to rapidly degrade fibrin and fibrinogen, the plasma proteins contributing to the formation of stable haemostatic clots. Plasminogen and Plasmin also have additional specialized physiological functions as disparate as wound healing, tissue regeneration and reproduction, with or without the participation of other factors.
EACA and TXA are known to bind to Plasminogen, Plasmin, and to numerous plasma proteins which share certain common structural features. The common structural features in all these proteins are known as “Kringles.” Kringles are protein chains consisting of approximately 80 to 100 amino acids of highly homologous sequences, held together by three disulfide linkages, which altogether impart a characteristic three-dimensional structure to these components of any native protein containing them. Typically, proteins containing Kringles have some functional association with Fibrin(ogen) and the Fibrin forming and degrading systems. Further, physiologically relevant proteolytic fragments of Plasmin(ogen), generated in normal metabolism and containing two or more Kringles, are known as Angiostatins, since they function as inhibitors of vascular growth.
Well before its structural elucidation, it was known that both Plasminogen and Plasmin bound to single-chain omega amino carboxylic acids, with 5, 6 or 7 amino-pentanoic, hexanoic or heptanoic acids being optimal in their ability to bind to or affect Plasmin(ogen) function. Detailed structure-activity studies led to identification, first of EACA and later TXA as then optimal pharmaceutical agents for moderating Plasmin mediated Fibrinolysis.
Aminocaproic acid (6-aminohexanoic acid) is a derivative and analogue of the amino acid lysine, which makes it an effective inhibitor or ligand for enzymes that bind that particular residue. Such enzymes include proteolytic enzymes like Plasmin, the enzyme responsible for fibrinolysis. For this reason, it is effective in treatment of certain bleeding disorders that can be given orally or intravenously. As an antifibrinolytic agent, aminocaproic acid works by blocking the breakdown of blood clots. It is useful for preventing and treating severe bleeding in patients with medical conditions that cause blood clots to dissolve faster than normal and lead to severe bleeding, including: hemophilia; aplastic anemia; lung, prostate, stomach and cervical cancer; cirrhosis; and certain complications of surgery.
Aminocaproic acid is FDA-approved for enhancing hemostasis when fibrinolysis contributes to bleeding. In life-threatening situations, transfusion of appropriate blood products and other emergency measures may be required. Fibrinolytic bleeding may frequently be associated with surgical complications following heart surgery (with or without cardiac bypass procedures) and portacaval shunt; hematological disorders such as amegakaryocytic thrombocytopenia (accompanying aplastic anemia); acute and life-threatening abruptio placentae; hepatic cirrhosis; and neoplastic disease such as carcinoma of the prostate, lung, stomach, and cervix. Urinary fibrinolysis, usually a normal physiological phenomenon, may contribute to excessive urinary tract fibrinolytic bleeding associated with surgical hematuria (following prostatectomy and nephrectomy) or nonsurgical hematuria (accompanying polycystic or neoplastic diseases of the genitourinary system). Topical gel (CAPROGEL) is FDA-approved for treatment of traumatic hyphema of the eye.
Tranexamic acid [trans-4-(aminomethyl)cyclohexanecarboxylic acid] is another synthetic analog of the amino acid lysine. It is used to treat or prevent excessive blood loss during surgery and in various medical conditions or disorders (helping hemostasis). It is an antifibrinolytic that inhibits the activation of plasminogen to plasmin, by binding to specific sites of both plasminogen and plasmin, a molecule responsible for the degradation of fibrin, a protein that forms the framework of blood clots. Tranexamic acid has roughly eight times the antifibrinolytic activity as aminocaproic acid, and is frequently used in surgeries with high risk of blood loss such as cardiac, liver, vascular and large orthopedic procedures.
Tranexamic acid 500 mg Tablets are FDA-approved for short term use for haemorrhage or risk of haemorrhage in those with increased fibrinolysis or fibrinogenolysis. Local fibrinolysis as occurs in the following conditions: prostatectomy and bladder surgery, menorrhagia, epistaxis, conisation of the cervix, traumatic hyphaema, management of dental extraction in haemophiliacs, and hereditary angioneurotic oedema. CYKLOKAPRON Injection is indicated in patients with hemophilia for short-term use (two to eight days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction.
Other antifibrinolytic compounds are described in the following patents and patent applications:
U.S. Pat. No. 3,526,657 to Merck discloses “the compound 4-aminomethylbicyclo [2.2.2]oct-2-ene-1-carboxylic acid having antifibrinolytic properties and being capable of counteracting certain hemorrhagic conditions and other disorders resulting from a pathological fibrinolytic state in patients.”
U.S. Pat. No. 3,634,499 to Merck discloses “the compounds 4-aminomethylbicyclo-[2.2.1]-heptane 1-carboxylic acid, 4-aminomethylbicyclo-[2.2.2]-octane-1-carboxylic acid, 5-aminomethylbicyclo-[3 2.2]-nonane-1-carboxylic acid and the corresponding 2,5 and 6,8-diketo compounds respectively are useful in antifibrinolytic compounds.”
U.S. Pat. No. 3,641,128 to Merck discloses “the compound 4-(a-amino lower alkyl)bicyclo-[2.2.2]-octane-1-carboxylic acid and the pharmaceutically acceptable salts thereof are useful as antifibrinolytic compounds.”
U.S. Pat. No. 3,641,129 to Merck discloses “the compound 4-aminomethylbicyclo-[2,2,2]-octanel-acetic acid and the pharmaceutically acceptable salts thereof are useful as and fibrinolytic compounds.”
U.S. Pat. No. 3,754,085 discloses “novel substituted or unsubstituted benzene and cyclohexane phosphonic acids. The phosphonic acids disclosed herein are potent anti-fibrinolytic agents. Also included herein are pharmaceutical compositions containing said phosphonic acid compounds as an active ingredient and methods of treating fibrinolytic states in patients by administering said compounds. Further encompassed is a substituted benzene phosphonic acid known to the art having novel anti-fibrinolytic activity.”
U.S. Pat. No. 3,920,833 to Stanley Drug Products discloses “a new class of synthetic antifibrinolytic agents is provided herein. Certain omega-aminoalkanesulfonic acids have been found to exhibit potent antifibrinolytic activities.”
U.S. Pat. No. 4,689,346 to Laboratorio Fides discloses “compounds for effecting hemostatic and antifibrinolytic action, namely a 1-acylamino naphthalene-4 sulphonic acid derivative and compositions and method of achieving such action.”
WO2014012964 to Prayecto De Biomedicina Cima discloses “spirocyclic compounds of formula (I), a process for their preparation, as well as to the intermediates used in this process. It also relates to pharmaceutical or veterinary compositions containing them, and to their use in medicine, in particular as antifibrinolytic and antihemorrhagic agents.”
There is still a need for improved antifibrinolytic compounds with better biological activities and/or reduced potential for side effects (such as thrombolytic complications) to treat subjects experiencing bleeding episodes, including subjects where the bleeding episodes are due to surgery, trauma, or other forms of tissue damage, as well as in clinical scenarios characterized by excessive fibrinolysis.